PROJECT ABSTRACT Persistence of childhood asthma into adult life has been conclusively linked to long-term lung function deficits and an increased susceptibility to non-fully reversible airflow limitation, the hallmark of chronic obstructive pulmonary disease. Yet, at the present time there are neither established prediction models nor available biomarkers for early risk identification of long-term sequelae in childhood asthma. In preliminary studies, we found early levels of circulating CC16 ? a pneumoprotein that is produced mainly by club cells in the distal airways and can be measured in circulation ? to be associated with resilience to subsequent lung function deficits and persistent asthma. Of note, these effects were independent of known risk factors for persistent disease. In addition, we found CC16-/- mice to have lung function deficits, airway alterations, and susceptibility to infections by Mycoplasma pneumoniae as compared with wild-type animals. These findings support CC16 in early school age as a strong and independent factor for resilience to persistent disease and long-term sequelae in children with asthma, and suggest that CC16 may exert these effects by modulating susceptibility and responses to airway infections. The present proposal addresses 1) the identification of early determinants of circulating CC16 levels by school-age; 2) the value of levels and trajectories of circulating CC16 in childhood as predictors of persistence and severity of asthma into adult life; and 3) the evaluation of airway responses to asthma pathogens as a potential mechanism mediating CC16 effects on persistent disease.